Monomaleimide-functionalized platinum compounds for cancer therapy

Abstract

The present invention relates to novel monomaleimide-functionalized platinum compounds of formula (I), including in particular novel monomaleimide-functionalized oxaliplatin and carboplatin derivatives, as well as their use as medicaments, particularly for the treatment or prevention of cancer. ##STR00001##

Claims

1. A method of treating cancer, wherein the cancer is selected from the group consisting of colon cancer, melanoma, leukemia, ovarian cancer, cervical cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, head and/or neck cancer, head and neck squamous cell carcinoma, breast cancer, and triple-negative breast cancer, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof to a subject in need thereof, ##STR00055## wherein: R.sup.1 and R.sup.2 are joined together to form a moiety (A2) or (A3): ##STR00056## R.sup.3 and R.sup.4 are joined together to form a moiety (B1), or R.sup.3 is a moiety (B2) and R.sup.4 is —NH.sub.3, or R.sup.3 and R.sup.4 are each —NH.sub.3: ##STR00057## R.sup.5 is —N(R.sup.51)— or —CH.sub.2—; R.sup.51 is hydrogen or C.sub.1-8 alkyl; R.sup.6 is C.sub.1-8 alkylene, wherein one or two —CH.sub.2— units comprised in said C.sub.1-8 alkylene are each optionally replaced by a group independently selected from the group consisting of —O—, —CO—, —C(═O)O—, —O—C(═O)—, —N(R.sup.61)—, —N(R.sup.61)—CO—, —CO—N(R.sup.61)—, arylene, and heteroarylene, wherein said arylene and said heteroarylene are each optionally substituted with one or more groups R.sup.62; each R.sup.61 is independently selected from the group consisting of hydrogen and C.sub.1-8 alkyl; each R.sup.62 is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, —(C.sub.0-3 alkylene)-OH, —(C.sub.0-3 alkylene)-O(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-SH, —(C.sub.0-3 alkylene)-S(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-NH.sub.2, —(C.sub.0-3 alkylene)-NH(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-halogen, —(C.sub.0-3 alkylene)-(C.sub.1-8 haloalkyl), —(C.sub.0-3 alkylene)-CF.sub.3, —(C.sub.0-3 alkylene)-CN, —(C.sub.0-3 alkylene)-CHO, —(C.sub.0-3 alkylene)-CO—(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-COOH, —(C.sub.0-3 alkylene)-CO—O—(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-O—CO—(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-CO—NH.sub.2, —(C.sub.0-3 alkylene)-CO—NH(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-CO—N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-NH—CO—(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-N(C.sub.1-8 alkyl)-CO—(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-SO.sub.2—NH.sub.2, —(C.sub.0-3 alkylene)-SO.sub.2—NH(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-SO.sub.2—N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-NH—SO.sub.2—(C.sub.1-8 alkyl), and —(C.sub.0-3 alkylene)-N(C.sub.1-8 alkyl)-SO.sub.2—(C.sub.1-8 alkyl); R.sup.7 is selected from the group consisting of hydrogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —O—(C.sub.1-8 alkyl), —O—(C.sub.2-8 alkenyl), —O—(C.sub.2-8 alkynyl), —O-cycloalkyl, —O-heterocycloalkyl, —O-aryl, —O-heteroaryl, —N(R.sup.71)—(C.sub.1-8 alkyl), —N(R.sup.71)—(C.sub.2-8 alkenyl), —N(R.sup.71)—(C.sub.2-8 alkynyl), —N(R.sup.71)-cycloalkyl, —N(R.sup.71)-heterocycloalkyl, —N(R.sup.71)-aryl, and —N(R.sup.71)-heteroaryl, wherein said C.sub.1-8 alkyl or the C.sub.1-8 alkyl moiety comprised in any of the aforementioned groups, said C.sub.2-8 alkenyl or the C.sub.2-8 alkenyl moiety comprised in any of the aforementioned groups, and said C.sub.2-8 alkynyl or the C.sub.2-8 alkynyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups R.sup.72, and further wherein said cycloalkyl or the cycloalkyl moiety comprised in any of the aforementioned groups, said heterocycloalkyl or the heterocycloalkyl moiety comprised in any of the aforementioned groups, said aryl or the aryl moiety comprised in any of the aforementioned groups, and said heteroaryl or the heteroaryl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups R.sup.73; each R.sup.71 is independently selected from the group consisting of hydrogen and C.sub.1-8 alkyl; each R.sup.72 is independently selected from the group consisting of —OH, —O(C.sub.1-8 alkyl), —SH, —S(C.sub.1-8 alkyl), —NH.sub.2, —NH(C.sub.1-8 alkyl), —N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), halogen, C.sub.1-8 haloalkyl, —CF.sub.3, —CN, —CHO, —CO—(C.sub.1-8 alkyl), —COOH, —CO—O—(C.sub.1-8 alkyl), —O—CO—(C.sub.1-8 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-8 alkyl), —CO—N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), —NH—CO—(C.sub.1-8 alkyl), —N(C.sub.1-8 alkyl)-CO—(C.sub.1-8 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-8 alkyl), —SO.sub.2—N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), —NH—SO.sub.2—(C.sub.1-8 alkyl), and —N(C.sub.1-8 alkyl)-SO.sub.2—(C.sub.1-8 alkyl); each R.sup.73 is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, —(C.sub.0-3 alkylene)-OH, —(C.sub.0-3 alkylene)-O(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-SH, —(C.sub.0-3 alkylene)-S(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-NH.sub.2, —(C.sub.0-3 alkylene)-NH(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-halogen, —(C.sub.0-3 alkylene)-(C.sub.1-8 haloalkyl), —(C.sub.0-3 alkylene)-CF.sub.3, —(C.sub.0-3 alkylene)-CN, —(C.sub.0-3 alkylene)-CHO, —(C.sub.0-3 alkylene)-CO—(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-COOH, —(C.sub.0-3 alkylene)-CO—O—(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-O—CO—(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-CO—NH.sub.2, —(C.sub.0-3 alkylene)-CO—NH(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-CO—N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-NH—CO—(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-N(C.sub.1-8 alkyl)-CO—(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-SO.sub.2—NH.sub.2, —(C.sub.0-3 alkylene)-SO.sub.2—NH(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-SO.sub.2—N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), —(C.sub.0-3 alkylene)-NH—SO.sub.2—(C.sub.1-8 alkyl), and —(C.sub.0-3 alkylene)-N(C.sub.1-8 alkyl)-SO.sub.2—(C.sub.1-8 alkyl); each R.sup.8 is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, —OH, —O—(C.sub.1-8 alkyl), —SH, —S—(C.sub.1-8 alkyl), —NH.sub.2, —NH(C.sub.1-8 alkyl), —N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), halogen, C.sub.1-8 haloalkyl, —CF.sub.3, —CN, —CHO, —CO—(C.sub.1-8 alkyl), —COOH, —CO—O—(C.sub.1-8 alkyl), —O—CO—(C.sub.1-8 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-8 alkyl), —CO—N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), —NH—CO—(C.sub.1-8 alkyl), —N(C.sub.1-8 alkyl)-CO—(C.sub.1-8 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-8 alkyl), —SO.sub.2—N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), —NH—SO.sub.2—(C.sub.1-8 alkyl), and —N(C.sub.1-8 alkyl)-SO.sub.2—(C.sub.1-8 alkyl); each R.sup.9 is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, —OH, —O—(C.sub.1-8 alkyl), —SH, —S—(C.sub.1-8 alkyl), —NH.sub.2, —NH(C.sub.1-8 alkyl), —N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), halogen, C.sub.1-8 haloalkyl, —CF.sub.3, —CN, —CHO, —CO—(C.sub.1-8 alkyl), —COOH, —CO—O—(C.sub.1-8 alkyl), —O—CO—(C.sub.1-8 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-8 alkyl), —CO—N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), —NH—CO—(C.sub.1-8 alkyl), —N(C.sub.1-8 alkyl)-CO—(C.sub.1-8 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-8 alkyl), —SO.sub.2—N(C.sub.1-8 alkyl)(C.sub.1-8 alkyl), —NH—SO.sub.2—(C.sub.1-8 alkyl), and —N(C.sub.1-8 alkyl)-SO.sub.2—(C.sub.1-8 alkyl); n is an integer of 0 to 8; and m is an integer of 0 to 6.

2. The method of claim 1, wherein R.sup.5 is —NH—, —N(—CH.sub.3)— or —N(—CH.sub.2CH.sub.3)—.

3. The method of claim 1, wherein R.sup.6 is selected from the group consisting of —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, and —(CH.sub.2).sub.5—.

4. The method of claim 1, wherein R.sup.5 is —NH—, and R.sup.6 is —(CH.sub.2).sub.2—.

5. The method of claim 1, wherein R.sup.7 is C.sub.1-5 alkyl.

6. The method of claim 1, wherein R.sup.7 is —CH.sub.3.

7. The method of claim 1, wherein n and m are each 0.

8. The method of claim 1, wherein R.sup.3 and R.sup.4 are joined together to form a moiety (B1), wherein n is 1, and wherein R.sup.8 is methyl.

9. The method of claim 1, wherein R.sup.1 and R.sup.2 are joined together to form a moiety (A2), and wherein R.sup.3 and R.sup.4 are joined together to form a moiety (B1).

10. The method of claim 1, wherein R.sup.1 and R.sup.2 are joined together to form a moiety (A2), and wherein R.sup.3 and R.sup.4 are each —NH.sub.3.

11. The method of claim 1, wherein R.sup.1 and R.sup.2 are joined together to form a moiety (A3).

12. The method of claim 1, wherein R.sup.1 and R.sup.2 are joined together to form a moiety (A2), R.sup.3 is a moiety (B2) and R.sup.4 is —NH.sub.3.

13. The method of claim 1, wherein R.sup.1 and R.sup.2 are joined together to form a moiety (A2); R.sup.5 is —NH—, —N(—CH.sub.3)— or —N(—CH.sub.2CH.sub.3)—; R.sup.6 is selected from the group consisting of —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, and —(CH.sub.2).sub.5—; R.sup.7 is C.sub.1-5 alkyl; and m is 0.

14. The method of claim 13, wherein R.sup.3 and R.sup.4 are each —NH.sub.3.

15. The method of claim 1, wherein the compound of formula (I) is a compound having any one of the following formulae: ##STR00058## ##STR00059## ##STR00060## or a pharmaceutically acceptable salt or hydrate thereof.

16. The method of claim 1, wherein the compound of formula (I) is a compound having the following formula: ##STR00061## or a pharmaceutically acceptable salt or hydrate thereof.

17. The method of claim 13, wherein the compound of formula (I) or hydrate thereof is not in the form of a salt.

18. The method of claim 14, wherein the compound of formula (I) or hydrate thereof is not in the form of a salt.

19. The method of claim 15, wherein the compound of formula (I) or hydrate thereof is not in the form of a salt.

20. The method of claim 16, wherein the compound of formula (I) or hydrate thereof is not in the form of a salt.

21. A method of treating cancer, wherein the cancer is selected from the group consisting of colon cancer, melanoma, leukemia, ovarian cancer, cervical cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, head and/or neck cancer, head and neck squamous cell carcinoma, breast cancer, and triple-negative breast cancer, the method comprising administering a compound having the following formula: ##STR00062## or a hydrate thereof to a subject in need thereof.

22. The method of claim 21, wherein the cancer is colon cancer, melanoma, or leukemia.

23. The method of claim 1, wherein the cancer is colon cancer, melanoma, or leukemia.

24. The method of claim 1, wherein the method comprises administering said compound in combination with an antimitotic agent which is selected from the group consisting of paclitaxel, nab-paclitaxel, docetaxel, larotaxel, ortataxel, and tesetaxel.

25. The method of claim 1, wherein the method comprises administering said compound in combination with folinic acid and 5-fluorouracil.

26. The method of claim 1, wherein the method comprises administering said compound in combination with an immunooncology therapeutic which is an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-TIM3 antibody, an anti-LAG3 antibody, an anti-OX4 antibody, an anti-CSF1R antibody, an anti-IDO antibody, or an anti-CD40 antibody.

27. The method of claim 1, wherein the subject is a human.

Description

(1) The invention is also described by the following illustrative figures. The appended figures show:

(2) FIGS. 1A-G: Superior anticancer activity of KP2299 against CT-26 colon cancer cells in vivo. KP2299 is compared against (FIG. 1A) oxaliplatin, (FIG. 1B) the oxaliplatin-releasing bismaleimide platinum(IV) drug KP2156 and (FIG. 1C) the oxaliplatin-releasing monomaleimide analogue KP2260. Data in FIGS. 1A-C are pooled from several independent experiments. (FIG. 1D) shows data from an experiment regarding a comparison of the cisplatin-releasing monomaleimide analogue KP2372 with cisplatin. (FIG. 1E) and (FIG. 1F) show data from an experiment regarding a comparison of the cisplatin-releasing monomaleimide complex KP2540 and the oxaliplatin-derivate KP2541 (without NH-group in the linker). (FIG. 1G) shows data from one experiment regarding KP2552 (with a 4-methyl-1,2-cyclohexanediamine ligand) and the carboplatin-releasing complex KP2551 in comparison to carboplatin. All experiments have been performed in male Balb/c mice and the control (0.9% NaCl) was treated according to the KP2299 and KP2156 solvent.

(3) FIGS. 2A-D: Impact of gender on the anticancer activity of KP2299 against CT-26 colon cancer cells in vivo. (FIG. 2A) and (FIG. 2B) show tumor burden and survival, respectively, in male animals, while in (FIG. 2C) and (FIG. 2D) data from female mice is shown. In (FIG. 2A) and (FIG. 2B) control mice were treated according to the KP2299 solvent (0.9% NaCl) and in (FIG. 2C) and (FIG. 2D) the control group was treated with 5% glucose according to the oxaliplatin solvent.

(4) FIG. 3: Superior anticancer activity of KP2299 against B16 melanoma cells in vivo. KP2299 is compared against oxaliplatin in male C57/B6JRj mice and the control was treated according to the KP2299 solvent (0.9% NaCl).

(5) FIG. 4: Anticancer activity of KP2299, oxaliplatin, KP2372 and cisplatin against leukemic L1210 cells in vivo. The figure shows data pooled together from several independent experiments.

(6) FIG. 5: Hydrolytic stability of KP2299 in buffered aqueous solution at different pH values determined by RP-HPLC.

(7) The invention will now be described by reference to the following examples, which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.

EXAMPLES

(8) The compounds described in this section are defined by their chemical formulae and their corresponding chemical names. In case of conflict between any chemical formula and the corresponding chemical name indicated herein, the present invention relates to both the compound defined by the chemical formula and the compound defined by the chemical name, and particularly relates to the compound defined by the chemical formula.

Example 1: Synthesis of Monomaleimide-Functionalized Platinum Compounds

(9) ##STR00048##

(10) ##STR00049##

(11) ##STR00050##

(12) ##STR00051##

(13) Materials and Methods:

(14) Potassium tetrachloridoplatinate (K.sub.2PtCl.sub.4) was purchased from Johnson Matthey (Switzerland). Water for synthesis was taken from a reverse osmosis system and distilled twice before use. For HPLC Milli-Q water (18.2 MΩ.Math.cm, Merck Milli-Q Advantage, Darmstadt, Germany) was used. Other chemicals and solvents were purchased from commercial suppliers (Sigma Aldrich, Acros, Fluka and Fisher Scientific). The platinum(II) precursors cisplatin (1), oxaliplatin (2), (SP-4-2)-diamminediiodidoplatinum(II), (SP-4-3)-[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]oxalatoplatinum(II) (25) and carboplatin (28) were prepared according to literature-known procedures (cisplatin and (SP-4-2)-diamminediiodidoplatinum(II): Dhara, S. Ch. Indian J. Chem. 1970, 8(2), 193-194, oxaliplatin: Kidani, Y; Inagaki, K. J. Med. Chem. 1978, 21(12), 1315-1318, carboplatin: Rochon, F. D.; Gruia, L. M. Inorg. Chim. Acta 2000, 306, 193-204 and (SP-4-3)-[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]oxalatoplatinum(II): Abramkin, S. A.; Jungwirth, U.; Valiahdi, S. M.; Dworak, C.; Habala, L.; Meelich, K.; Berger, W.; Jakupec, M. A.; Hartinger, C. G.; Nazarov, A. A.; Galanski, M.; Keppler, B. K. J. Med. Chem. 2010, 53, 7356-7364). Thereafter, these were oxidized with hydrogen peroxide (50%) using either methanol (Dunham, S. O.; Larsen, R. D. Inorg. Chem. 1993, 32, 2049-2055) or acetic acid (Lee, Y.-A.; Jung, S. M.; Kang, S. W.; Jung, O.-S. Transition Met. Chem. 2004, 29, 710-713) as a solvent to yield the unsymmetrically oxidized platinum(IV) precursors 3-6, 26, 27 and 29. The maleimide- and succinimide-functionalized isocyanate ligands were prepared according to a recently published procedure (Pichler, V.; Mayr, J.; Heffeter, P.; Dömötör, O.; Enyedy, É. A.; Hermann, G.; Groza, D.; Kölensperger, G.; Galanski, M.; Berger, W.; Keppler, B. K.; Kowol, C. R. Chem. Commun. 2013, 49, 2049-2051) and the mixed anhydride ligands according to literature-known procedure (Cheronis, J. C.; Whalley, E. T.; Nguyen, K. T.; Eubanks, S. R.; Allen, L. G.; Duggan, M. J.; Loy, S. D.; Bonham, K. A.; Blodgett, J. K. J. Med. Chem. 1992, 35, 1563-1572). Compounds 7-14, 17-20, 22-24 and 30-31 were purified by preparative RP-HPLC using a Waters XBridge C18 column on an Agilent 1200 Series system. Milli-Q water, containing 0.1% formic acid and methanol or acetonitrile were used as eluents. Electrospray ionization (ESI) mass spectra were recorded on a Bruker amaZon SL ion trap mass spectrometer in positive and/or negative mode by direct infusion. High resolution mass spectra were measured on a Bruker maXis™ UHR ESI time of flight mass spectrometer. All mass spectra were recorded at the Mass Spectrometry Centre of the University of Vienna. .sup.1H-, .sup.13C-, .sup.15N-, and .sup.195Pt-one- and two-dimensional NMR spectra were recorded on a Bruker Avance III 500 MHz spectrometer at 500.10 (.sup.1H), 127.75 (.sup.13C), 50.68 (.sup.15N), and 107.51 (.sup.195Pt) MHz at 298 K. For .sup.1H- and .sup.13C-NMR spectra the solvent residual peak was taken as internal reference, whereas .sup.195Pt-shifts were referenced relative to external K.sub.2PtCl.sub.4 and .sup.15N-shifts relative to external NH.sub.4Cl. Elemental analysis measurements were performed on a Perkin Elmer 2400 CHN Elemental Analyzer at the Microanalytical Laboratory of the University of Vienna.

(15) General Procedure for the Synthesis of Compounds 7-14, 17-20, 22-24 and 30-31

(16) The unsymmetrically, oxidized platinum(IV) compound and the corresponding isocyanate (in the case of compounds 7-14, 17-20, 23-24 and 30-31) or the corresponding mixed anhydride (in case of compound 22) were transferred into a Schlenk tube and set under argon atmosphere. After the addition of dry DMF, the suspension was stirred overnight. Remaining precipitates were filtered off, before the DMF was removed under reduced pressure. The remains were taken up as a suspension in methanol and fully precipitated by addition of diethyl ether. After a few hours in the fridge, the crude product was filtered off, washed with diethyl ether and dried under reduced pressure. The crude product was taken up in water and filtered before it was purified by preparative RP-HPLC. Collected product fractions were lyophilized and dried in vacuo.

(OC-6-44)-Diamminedichloridomethoxido[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platinum(IV) (7; KP2298)

(17) The compound was synthesized from (OC-6-44)-diamminedichloridohydroxidomethoxidoplatinum(IV) (3; 140 mg, 0.40 mmol) and 1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione (2 eq., 134 mg, 0.80 mmol) in 3 mL DMF (abs.). Purification via preparative RP-HPLC, isocratic with 8% methanol, yielded a pale yellow solid. Yield: 70.5 mg (18%); .sup.1H-NMR (DMSO-d6): δ=6.98 (s, 2H, CH), 6.38 (s, 1H, NH), 6.17-5.73 (m, 6H, NH.sub.3), 3.46-3.36 (m, 2H, NCH.sub.2), 3.06-2.96 (m, 2H, NHCH.sub.2), 2.63 (br, 3H, CH.sub.3) ppm; .sup.13C-NMR (DMSO-d6): δ=171.1 (COCH), 164.8 (CONH), 134.5 (CH), 60.5 (CH.sub.3), 39.2 (NHCH.sub.2), 37.5 (NCH.sub.2) ppm; .sup.15N{.sup.1H}-NMR (DMSO-d6): δ=59.5 (NH), −31.7 (NH.sub.3) ppm; .sup.195Pt-NMR (DMSO-d6): δ=2642 (major), 2629 (minor) ppm; HRMS (ESI-TOF): calcd. for [C.sub.8H.sub.18Cl.sub.2N.sub.4O.sub.5Pt—Na.sup.+].sup.+: 536.0043, found: 536.0028; elemental analysis calcd. for C.sub.8H.sub.18Cl.sub.2N.sub.4O.sub.5Pt.0.5H.sub.2O: C: 18.36, H: 3.27, N: 10.71, O: 16.82, found: C: 18.38, H: 2.92, N: 10.32, O: 16.57.

(OC-6-44)-Acetatodiamminedichlorido[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platinum(IV) (8; KP2372)

(18) The compound was synthesized from (OC-6-44)-acetatodiamminedichloridohydroxidoplatinum(IV) (4; 450 mg, 1.20 mmol) and 1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione (2 eq., 398 mg, 2.39 mmol) in 5 mL DMF (abs.). Purification via preparative RP-HPLC, isocratic with 3% methanol, yielded a pale yellow solid. Yield: 267.0 mg (42%); .sup.1H-NMR (DMSO-d6): δ=6.98 (s, 2H, CH), 6.80-6.37 (m, 6H, NH.sub.3), 6.67 (br, 1H, NH), 3.45-3.37 (m, 2H, NCH.sub.2), 3.07-2.99 (m, 2H, NHCH.sub.2), 1.90 (s, 3H, CH.sub.3) ppm; .sup.13C-NMR (DMSO-d6): δ=178.2 (COCH.sub.3), 171.1 (COCH), 163.8 (CONH), 134.5 (CH), 38.9 (NHCH.sub.2), 37.4 (NCH.sub.2), 22.8 (CH.sub.3) ppm; .sup.15N{.sup.1H}-NMR (DMSO-d6): δ=59.2 (NH), −39.4 (NH.sub.3) ppm; .sup.195Pt-NMR (DMSO-d6): δ=2880 (major), 2860 (minor) ppm; HRMS (ESI-TOF): calcd. for [C.sub.9H.sub.18Cl.sub.2N.sub.4O.sub.6Pt—Na.sup.+].sup.+: 564.9944, found: 564.9977; elemental analysis calcd. for C.sub.9H.sub.18Cl.sub.2N.sub.4O.sub.6Pt-1.5H.sub.2O: C: 18.99, H: 3.36, N: 9.84, found: C: 18.73, H: 3.18, N: 9.70.

(OC-6-44)-Diamminedichloridomethoxido[2-(2,5-dioxopyrrolidin-1-yl)ethyl)carbamato]platinum(IV) (9)

(19) The compound was synthesized from (OC-6-44)-diamminedichloridohydroxidomethoxidoplatinum(IV) (3; 200 mg, 0.57 mmol) and 1-(2-isocyanatoethyl)pyrrolidine-2,5-dione (1.5 eq., 145 mg, 0.86 mmol) in 3 mL DMF (abs.). Purification via preparative RP-HPLC, isocratic with 5% methanol, yielded a pale yellow solid. Yield: 124.2 mg (42%); .sup.1H-NMR (DMSO-d6): δ=6.32 (s, 1H, NH), 6.20-5.70 (m, 6H, NH.sub.3), 3.47-3.29 (m, 2H, NCH.sub.2), 3.10-2.92 (m, 2H, NHCH.sub.2), 2.63 (br, 3H, CH.sub.3), 2.58 (br, 4H, COCH.sub.2) ppm; .sup.13C-NMR (DMSO-d6): δ=177.9 (COCH.sub.2), 164.9 (CONH), 60.5 (CH.sub.3), 38.3 (br, NHCH.sub.2, NCH.sub.2), 28.1 (COCH2) ppm; .sup.195Pt-NMR (DMSO-d6): δ=2642 (major), 2629 (minor) ppm; HRMS (ESI-TOF): calcd. for [C.sub.8H.sub.18Cl.sub.2N.sub.4O.sub.5Pt—Na.sup.+].sup.+: 538.0200, found: 538.0195; elemental analysis calcd. for C.sub.8H.sub.18Cl.sub.2N.sub.4O.sub.5Pt.0.5H.sub.2O: C: 18.32, H: 3.65, N: 10.69, found: C: 18.73, H: 3.66, N: 10.22.

(OC-6-44)-Acetatodiamminedichlorido[2-(2,5-dioxopyrrolidin-1-yl)ethyl)carbamato]platinum(IV) (10)

(20) The compound was synthesized from (OC-6-44)-acetatodiamminedichloridohydroxidoplatinum(IV) (4; 600 mg, 1.60 mmol) and 1-(2-isocyanatoethyl)pyrrolidine-2,5-dione (1.5 eq., 402 mg, 2.39 mmol) in 5 mL DMF (abs.). Purification via preparative RP-HPLC, with a gradient from 5-10.5% methanol in 10 min, yielded a pale yellow solid. Yield: 232.2 mg (27%); .sup.1H-NMR (DMSO-d6): δ=6.89-6.33 (m, 7H, NH.sub.3, NH), 3.41-3.34 (m, 2H, NCH.sub.2), 3.03 (q, J=6.2 Hz, 2H, NHCH.sub.2), 2.59 (br, 4H, COCH.sub.2), 1.90 (s, 3H, CH.sub.3) ppm; .sup.13C-NMR (DMSO-d6): δ=178.2 (COCH.sub.3), 177.8 (COCH.sub.2), 163.9 (CONH), 38.2 (NHCH.sub.2, NCH.sub.2), 28.1 (COCH.sub.2), 22.8 (CH.sub.3) ppm; .sup.195Pt-NMR (DMSO-d6): δ=2880 (major), 2859 (minor) ppm; HRMS (ESI-TOF): calcd. for [CH.sub.18Cl.sub.2N.sub.4O.sub.6Pt—Na.sup.+].sup.+: 567.0100, found: 567.0138; elemental analysis calcd. for C.sub.9H.sub.18Cl.sub.2N.sub.4O.sub.6Pt.H.sub.2O: C: 19.23, H: 3.59, N: 9.96, found: C: 19.17, H: 3.35, N: 9.88.

(OC-6-34)-[(1R,2R)-Cyclohexane-1,2-diamine]methoxidooxalato[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platinum(IV) (11; KP2260)

(21) The compound was synthesized from (OC-6-44)-[(1R,2R)-cyclohexane-1,2-diamine]hydroxidomethoxidooxalatoplatinum(IV) (5; 170 mg, 0.38 mmol) and 1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione (2 eq., 127 mg, 0.76 mmol) in 7 mL DMF (abs.). Purification via preparative RP-HPLC, with a gradient from 15-35% methanol in 10 min, yielded a white solid. Yield: 88.7 mg (38%); .sup.1H-NMR (DMSO-d6): δ=9.85-9.55 (m, 1H, NH.sub.2), 8.33-8.09 (m, 1H, NH.sub.2), 7.79-7.59 (m, 1H, NH.sub.2), 7.07-6.83 (m, 1H, NH.sub.2), 6.98 (s, 2H, COCH), 6.44 (s, 1H, NH), 3.55-3.45 (m, 1H, NCH.sub.2), 3.39-3.29 (m, 1H, NCH.sub.2), 3.15-3.05 (m, 1H, NHCH.sub.2), 3.00-2.90 (m, 1H, NHCH.sub.2), 2.63-2.43 (m, 2H, CH.sub.dach), 2.41 (s, 3H, CH.sub.3), 2.19-2.07 (m, 1H, CH.sub.2,dach), 2.07-1.96 (m, 1H, CH.sub.2,dach), 1.60-1.42 (m, 3H, CH.sub.2,dach), 1.39-1.27 (m, 1H, CH.sub.2,dach), 1.25-1.07 (m, 2H, CH.sub.2,dach) ppm; .sup.13C-NMR (DMSO-d6): δ=171.0 (COCH), 165.2 (CONH), 163.7 (CO.sub.ox), 163.6 (CO.sub.ox), 134.4 (COCH), 61.3 (CH.sub.dach), 59.5 (CH.sub.dach), 57.4 (CH.sub.3), 39.0 (NHCH.sub.2), 37.4 (NCH.sub.2), 30.6 (CH.sub.2,dach), 23.7 (CH.sub.2,dach), 23.6 (CH.sub.2,dach) ppm; .sup.15N{.sup.1H}-NMR (DMSO-d6): δ=60.9 (NH), −6.4 (NH.sub.2), −1.5 (NH.sub.2) ppm; .sup.195Pt-NMR (DMSO-d6): δ=3001 (major), 2995 (minor) ppm; HRMS (ESI-TOF): calcd. for [C.sub.16H.sub.24N.sub.4O.sub.9Pt—Na.sup.+].sup.+: 634.1089, found: 634.1089; elemental analysis calcd. for C.sub.16H.sub.24N.sub.4O.sub.9Pt.H.sub.2O: C: 30.53, H: 4.16, N: 8.90 found: C: 30.29, H: 4.08, N: 8.75.

(OC-6-34)-Acetato[(1R,2R)-cyclohexane-1,2-diamine]oxalato[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platinum(IV) (12, KP2299)

(22) The compound was synthesized from (OC-6-44)-acetato[(1R,2R)-cyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV) (6; 200 mg, 0.42 mmol) and 1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione (2 eq., 140 mg, 0.85 mmol) in 2 mL DMF (abs.). Purification via preparative RP-HPLC, isocratic with 15% methanol, yielded a white solid. Yield: 111.2 mg (41%); .sup.1H-NMR (DMSO-d6): δ=9.63 (bs, 1H, NH.sub.2), 8.74-8.00 (m, 3H, NH.sub.2), 6.99 (s, 2H, COCH), 6.79 (t, J=5.9 Hz, 1H, NH), 3.58-3.45 (m, 1H, NCH.sub.2), 3.42-3.29 (m, 1H, NCH.sub.2), 3.19-3.08 (m, 1H, NHCH.sub.2), 3.01-2.89 (m, 1H, NHCH.sub.2), 2.70-2.60 (m, 1H, CH.sub.dach), 2.60-2.50 (m, 1H, CH.sub.dach), 2.15 (bs, 2H, CH.sub.2,dach), 1.95 (s, 1H, CH.sub.3), 1.59-1.10 (m, 6H, CH.sub.2,dach) ppm; .sup.13C-NMR (DMSO-d6): δ=178.4 (COCH.sub.3), 171.0 (COCH), 164.2 (CONH), 163.3 (CO.sub.ox), 134.5 (COCH), 61.1 (CH.sub.dach), 60.7 (CH.sub.dach), 39.0 (NHCH.sub.2), 37.2 (NCH.sub.2), 31.0 (CH.sub.2,dach), 30.9 (CH.sub.2,dach), 23.5 (CH.sub.2,dach), 23.4 (CH.sub.2,dach), 22.9 (CH.sub.3) ppm; .sup.195Pt-NMR (DMSO-d6): δ=3236 (major), 3227 (minor) ppm; HRMS (ESI-TOF): calcd. for [C.sub.17H.sub.24N.sub.4O.sub.10Pt—Na.sup.+].sup.+: 662.1038, found: 662.1033; elemental analysis calcd. for C.sub.17H.sub.24N.sub.4O.sub.10Pt.H.sub.2O: C: 31.05, H: 3.99, N: 8.52, found: C: 30.96, H: 3.91, N: 8.44.

(OC-6-34)-[(1R,2R)-Cyclohexane-1,2-diamine]methoxidooxalato[2-(2,5-dioxopyrrolidin-1-yl)ethyl)carbamato]platinum(IV) (13)

(23) The compound was synthesized from (OC-6-44)-[(1R,2R)-cyclohexane-1,2-diamine]hydroxidomethoxidooxalatoplatinum(IV) (5; 200 mg, 0.45 mmol) and 1-(2-isocyanatoethyl)pyrrolidine-2,5-dione (2 eq., 151 mg, 0.90 mmol) in 3 mL DMF (abs.). Purification via preparative RP-HPLC, isocratic with 14% methanol, yielded a white solid. Yield: 118.1 mg (43%); 1H-NMR (DMSO-d6): δ=9.84-9.42 (m, 1H, NH.sub.2), 8.20 (bs, 1H, NH.sub.2), 7.70 (bs, 1H, NH.sub.2), 6.98 (bs, 1H, NH.sub.2), 6.43 (t, J=5.9 Hz, 1H, NH), 3.51-3.41 (m, 1H, NCH.sub.2), 3.35-3.25 (m, 1H, NCH.sub.2), 3.13-2.94 (m, 2H, NHCH.sub.2), 2.62-2.55 (m, 1H, CH.sub.dach), 2.58 (s, 4H, COCH.sub.2), 2.54-2.46 (m, 1H, CH.sub.dach), 2.41 (s, 3H, CH.sub.3), 2.17-2.08 (m, 1H, CH.sub.2,dach), 2.07-1.96 (m, 1H, CH.sub.2,dach), 1.58-1.42 (m, 3H, CH.sub.2,dach), 1.41-1.27 (m, 1H, CH.sub.2,dach), 1.22-1.08 (m, 2H, CH.sub.2,dach) ppm; .sup.13C-NMR (DMSO-d6): δ=177.7 (COCH.sub.2), 165.3 (CONH), 163.7 (CO.sub.ox), 163.6 (CO.sub.ox), 61.3 (CH.sub.dach), 59.5 (CH.sub.dach), 57.4 (CH.sub.3), 38.2 (NHCH.sub.2), 38.1 (NCH.sub.2), 30.6 (CH.sub.2,dach), 28.0 (CH.sub.2,dach), 23.7 (CH.sub.2,dach), 23.6 (CH.sub.2,dach) ppm; .sup.195Pt-NMR (DMSO-d6): δ=3000 (major), 2992 (minor) ppm; HRMS (ESI-TOF): calcd. for [C.sub.16H.sub.26N.sub.4O.sub.9Pt—Na.sup.+].sup.+: 636.1245, found: 636.1249; elemental analysis calcd. for C.sub.16H.sub.26N.sub.4O.sub.9Pt.H.sub.2O: C: 30:43, H: 4:47, N: 8:87, found: C: 30:26, H: 4:59, N: 8:72.

(OC-6-34)-Acetato[(1R,2R)-cyclohexane-1,2-diamine]oxalato[2-(2,5-dioxopyrrolidin-1-yl)ethyl)carbamato]platinum(IV) (14)

(24) The compound was synthesized from (OC-6-44)-acetato[(1R,2R)-cyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV) (6; 200 mg, 0.42 mmol) and 1-(2-isocyanatoethyl)pyrrolidine-2,5-dione (1.5 eq., 107 mg, 0.63 mmol) in 4 mL DMF (abs.). Purification via preparative RP-HPLC, isocratic with 17% methanol, yielded a white solid. Yield: 92.2 mg (18%); .sup.1H-NMR (DMSO-d6): δ=9.76-9.25 (m, 1H, NH.sub.2), 8.74-8.02 (m, 3H, NH.sub.2), 6.76 (t, J=6.0 Hz, 1H, NH), 3.53-3.42 (m, 1H, NCH.sub.2), 3.37-3.25 (m, 1H, NCH.sub.2), 3.14-2.95 (m, 2H, NHCH.sub.2), 2.71-2.62 (m, 1H, CH.sub.dach), 2.62-2.53 (m, 1H, CH.sub.dach), 2.58 (s, 4H, COCH.sub.2), 2.14 (bs, 2H, CH.sub.2,dach), 1.95 (s, 1H, CH.sub.3), 1.57-1.33 (m, 4H, CH.sub.2,dach), 1.29-1.10 (m, 2H, CH.sub.2,dach) ppm; .sup.13C-NMR (DMSO-d6): δ=178.4 (COCH.sub.3), 177.7 (COCH), 164.2 (CONH), 163.3 (CO.sub.ox), 61.1 (CH.sub.dach), 60.8 (CH.sub.dach), 38.1 (NHCH.sub.2), 37.9 (NCH.sub.2), 31.0 (CH.sub.2,dach), 30.9 (CH.sub.2,dach), 28.0 (COCH.sub.2), 23.5 (CH.sub.2,dach), 23.4 (CH.sub.2,dach), 22.9 (CH.sub.3) ppm; .sup.195Pt-NMR (DMSO-d6): δ=3236 (major), 3225 (minor) ppm; HRMS (ESI-TOF): calcd. for [C.sub.17H.sub.26N.sub.4O.sub.10Pt—Na.sup.+].sup.+: 664.1194, found: 664.1189; elemental analysis calcd. for C.sub.17H.sub.26N.sub.4O.sub.10Pt-1.5H.sub.2O: C: 30.54, H: 4.37, N: 8.38, found: C: 30.37, H: 3.98, N: 8.24.

(SP-4-2)-Diammineoxalatoplatinum(II) (15)

(25) 692 mg of (SP-4-2)-diamminediiodidoplatinum(II) (1.43 mmol) were suspended in 13 mL triple distilled water and 475 mg AgNO.sub.3 (1.95 eq., 2.80 mmol) were added. The suspension was stirred vigorously for 8 h. Thereafter, the precipitate was filtered off, 257.6 mg potassium oxalate (0.975 eq., 1.40 mmol) were added and the reaction mixture was stirred overnight. After 1 h at 4° C., the white product was filtered off, washed with small amounts of cold triple distilled water, and dried over P.sub.2O.sub.5 under reduced pressure. Yield: 434.1 mg (98%).

(OC-6-44)-Acetatodiamminehydroxidooxalatoplatinum(IV) (16)

(26) 200 mg of (SP-4-2)-diammineoxalatoplatinum(II) (15) (0.63 mmol) were suspended in 35 mL glacial acetic acid. After the addition of 715 μL H.sub.2O.sub.2 (50%) (20 eq., 12.61 mmol), the suspension was stirred in the dark for 2 days. The white precipitate was filtered off, washed with glacial acetic acid and diethyl ether and dried under reduced pressure. The product was used without further purification. Yield: 175 mg (71%).

(OC-6-34)-Acetatodiammineoxalato[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platinum(IV) (17)

(27) The compound was synthesized from (OC-6-44)-acetatodiamminehydroxidooxalatoplatinum(IV) (16; 66.3 mg, 0.17 mmol) and 1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione (2 eq., 56.0 mg, 0.34 mmol) in 5 mL DMF (abs.) according to the general procedure. Purification via preparative RP-HPLC, isocratic with 3% methanol, yielded a white solid. Yield: 17.5 mg (20%); .sup.1H-NMR (DMSO-d6): δ=6.99 (s, 2H, CH), 6.85-6.39 (m, 6H, NH.sub.3), 6.82 (br, 1H, NH), 3.42 (t, J=6.5 Hz, 2H, NCH.sub.2), 3.10-3.00 (m, 2H, NHCH.sub.2), 1.92 (s, 3H, CH.sub.3) ppm; .sup.13C-NMR (DMSO-d6): δ=177.8 (COCH.sub.3), 171.5 (COCH), 164.2 (CO.sub.ox), 163.6 (CONH), 135.0 (CH), 39.5 (NHCH.sub.2), 37.9 (NCH.sub.2), 22.8 (CH.sub.3) ppm; .sup.195Pt-NMR (DMSO-d6): δ=3393 (major), 3383 (minor) ppm; HRMS (ESI-TOF): calcd. for [C.sub.11H.sub.16N.sub.4O.sub.10Pt—Na.sup.+].sup.+: 582.0406, found: 582.0417.

(OC-6-54-A)-Acetato[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV) (26) and (OC-6-54-C)-Acetato[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV) (27)

(28) The compound mixture was synthesized out of 51.5 mg of (SP-4-3)-[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]oxalatoplatinum(II) (25, 125.2 μmol) which was suspended in 2 mL glacial acetic acid. After the addition of 71.0 μL H.sub.2O.sub.2 (50%) (10 eq. 1.25 mmol), the suspension was stirred in the dark for 16 h. The remaining solution was concentrated under reduced pressure and the product precipitated by the addition of MeOH and diethyl ether. The white product was filtered off, washed with diethyl ether and dried under reduced pressure. The product was used without further purification. Yield: 56.0 mg (92%).

Mixture of (OC-6-35-A)-Acetato[(1R,2R,4R)-4-methylcyclohexan-1,2-diamin]oxalato[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platin(IV) (18) and (OC-6-35-C)-Acetato[(1R,2R,4R)-4-methylcyclohexan-1,2-diamin]oxalato[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platin(IV) (19)

(29) The compound mixture was synthesized from the racemic mixture of (OC-6-54-A/C)-acetato[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV) (26/27; 50 mg, 102.59 μmol) and 1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione (3 eq., 51.1 mg, 307.78 μmol) in 1.5 mL DMF (abs.) according to the general procedure. Purification via preparative RP-HPLC, with a gradient from 23-33% methanol in 20 min, yielded a white solid. Yield: 16.7 mg (25%); 1H-NMR (DMSO-d6): δ=9.59 (br, 1H, NH.sub.2), 8.53 (br, 1H, NH.sub.2), 8.30 (br, 1H, NH.sub.2), 8.20 (br, 1H, NH.sub.2), 7.00 (s, 2H, COCH), 6.80 (br, 1H, NH), 3.58-3.46 (m, 1H, NCH.sub.2), 3.41-3.28 (m, 1H, NCH.sub.2), 3.19-3.09 (m, 1H, NHCH.sub.2), 3.04-2.92 (m, 1H, NHCH.sub.2), 2.80-2.51 (m, 2H, CH.sub.dach), 2.11 (br, 2H, CH.sub.2,dach), 1.96 (s, 1H, CH.sub.3), 1.60-1.37 (m, 3H, CH.sub.2,dach), 1.23-1.09 (m, 1H, CH.sub.2,dach), 1.04-0.86 (m, 1H, CH.sub.dach), 0.95 (d, J=6.4 Hz, 3H, CH.sub.3,dach) ppm; HRMS (ESI-TOF): calcd. for [C.sub.18H.sub.26N.sub.4O.sub.10Pt—Na.sup.+].sup.+: 676.1190, found: 676.1190; elemental analysis calcd. for C.sub.18H.sub.26N.sub.4O.sub.10Pt.H.sub.2O: C: 32.63, H: 4.11, N: 8.47, found: C: 32.69, H: 4.12, N: 8.15. If desired, compounds 18 and 19 can be separated using, e.g., chiral column chromatography (particularly chiral HPLC).

(SP-4-2)-Diamminecyclobutane-1,1-dicarboxylatoplatinum(II) (28)

(30) 1.894 g of (SP-4-2)-diamminediiodidoplatinum(II) (3.92 mmol) were suspended in 150 mL triple distilled water and 1.198 g Ag.sub.2SO.sub.4 (0.98 eq., 3.84 mmol) were added. The suspension was stirred vigorously for 4 h. Thereafter, the precipitate was filtered off, a solution of 635.9 mg cyclobutane-1,1-dicarboxylic acid (1.13 eq., 4.41 mmol) and 1.213 g Ba(OH).sub.2.8H.sub.2O (0.98 eq., 3.84 mmol) in 50 mL triple distilled water was added and the reaction mixture was stirred for another hour. After filtration, the solution was concentrated under reduced pressure and the product precipitated with MeOH. The white product was filtered off, washed with MeOH and dried under reduced pressure. Yield: 1.214 g (85%).

(OC-6-44)-acetatodiamminecyclobutane-1,1-dicarboxylatohydroxidoplatinum(IV) (29)

(31) 300 mg of (SP-4-2)-diamminecyclobutane-1,1-dicarboxylatoplatinum(II) (28) (0.81 mmol) were suspended in 7 mL glacial acetic acid. After the addition of 458.0 μL H.sub.2O.sub.2 (50%) (10 eq. 8.08 mmol), the suspension was stirred in the dark for 2 days. The remaining solution was concentrated under reduced pressure and the product precipitated by the addition of MeOH and diethyl ether. The white product was filtered off, washed with diethyl ether and dried under reduced pressure. The product was used without further purification. Yield: 337.2 mg (93%).

(OC-6-34)-Acetatodiamminecyclobutane-1,1-dicarboxylato[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platinum(IV) (20; KP2551)

(32) The compound was synthesized from (OC-6-44)-acetatodiamminecyclobutane-1,1-dicarboxylatohydroxidoplatinum(IV) (29; 300.0 mg, 0.67 mmol) and 1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione (2 eq., 222.8 mg, 1.34 mmol) in 3 mL DMF (abs.) according to the general procedure. Purification via preparative RP-HPLC, isocratic with 7% acetonitrile, yielded a white solid. Yield: 50.6 mg (12%); .sup.1H-NMR (DMSO-d6): δ=6.99 (s, 2H, CH), 6.71-6.24 (m, 6H, NH.sub.3), 6.62 (br, 1H, NH), 3.42 (t, J=6.4 Hz, 2H, NCH.sub.2), 3.05 (q, J=6.4 Hz, 2H, NHCH.sub.2), 2.49 (t, J=8.0 Hz, 4H, CH.sub.2CCH.sub.2), 1.90 (s, 3H, CH.sub.3), 1.81 (quint, J=8.0 Hz, 2H, CH.sub.2CCH.sub.2) ppm; HRMS (ESI-TOF): calcd. for [C.sub.15H.sub.22N.sub.4O.sub.10Pt—Na.sup.+].sup.+: 636.0876, found: 636.0884; elemental analysis calcd. for C.sub.16H.sub.22N.sub.4O.sub.10Pt.H.sub.2O: C: 28.53, H: 3.83, N: 8.87, found: C: 28.62, H: 3.75, N: 8.64.

(OC-6-44)-Acetato[(1R,2R)-cyclohexane-1,2-diamine]oxalato[4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoato]platinum(IV) (22; KP2541)

(33) The compound was synthesized from (OC-6-44)-acetato[(1R,2R)-cyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV) (6; 150 mg, 317.7 μmol) and (isobutyl carbonic) 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoic anhydride (1.5 eq., 140 mg, 0.85 mmol) in 2 mL DMF (abs.) according to the general procedure. Purification via preparative RP-HPLC, with a gradient from 15-35% methanol in 20 min, yielded a white solid. Yield: 52.4 mg (26%); .sup.1H-NMR (DMSO-d6): δ=8.52-8.11 (m, 4H, NH.sub.2), 7.01 (s, 2H, COCH), 3.46-3.36 (m, 2H, NCH.sub.2), 2.67-2.51 (m, 2H, CH.sub.dach), 2.27 (t, J=7.3 Hz, 2H, COCH.sub.2), 2.18-2.06 (m, 2H, CH.sub.2,dach), 1.96 (s, 3H, CH.sub.3), 1.68 (quint, J=7.3 Hz, 2H, COCH.sub.2CH.sub.2), 1.56-1.35 (m, 4H, CH.sub.2,dach), 1.28-1.11 (m, 2H, CH.sub.2,dach) ppm; HRMS (ESI-TOF): calcd. for [C.sub.18H.sub.25N.sub.3O.sub.10Pt—Na.sup.+].sup.+: 661.1080, found: 661.1080; elemental analysis calcd. for C.sub.18H.sub.25N.sub.310Pt.H.sub.2O: C: 32.93, H: 4.15, N: 6.40, found: C: 33.02, H: 4.12, N: 6.33.

Mixture of (OC-6-35-A)-Acetato[(1R,2R,4R)-4-methylcyclohexan-1,2-diamin]oxalato[5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentylcarbamato]platin(IV) (23) and (OC-6-35-C)-Acetato[(1R,2R,4R)-4-methylcyclohexan-1,2-diamin]oxalato[5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentylcarbamato]platin(IV) (24)

(34) The compound mixture (KP2552) was synthesized from the racemic mixture of (OC-6-54-A/C)-acetato[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV) (26/27; 52.0 mg, 106.7 μmol) and 1-(5-isocyanatopentyl)-1H-pyrrole-2,5-dione (3 eq., 66.6 mg, 320.1 μmol) in 1.5 mL DMF (abs.) according to the general procedure. Purification via preparative RP-HPLC, with a gradient from 18-33% methanol in 30 min, yielded a white solid. Yield: 19.7 mg (27%); 1H-NMR (DMSO-d6): δ=9.62 (br, 1H, NH.sub.2), 8.55 (br, 1H, NH.sub.2), 8.25 (br, 2H, NH.sub.2), 7.01 (s, 2H, COCH), 6.78 (br, 1H, NH), 3.41-3.33 (m, 2H, NCH.sub.2), 2.96-2.77 (m, 2H, CH.sub.2), 2.71-2.48 (m, 2H, CH.sub.2,dach), 2.16-2.02 (m, 2H, CH.sub.2,dach), 1.96 (s, 1H, CH.sub.3), 1.57-1.25 (m, 7H, CH.sub.2,dach, CH.sub.2), 1.25-1.05 (m, 3H, CH.sub.2,dach, CH.sub.2), 1.01-0.84 (m, 1H, CH.sub.dach), 0.93 (d, J=6.3 Hz, 3H, CH.sub.3,dach) ppm; HRMS (ESI-TOF): calcd. for [C.sub.21H.sub.32N.sub.4O.sub.10Pt—Na.sup.+].sup.+: 718.1660, found: 718.1661; elemental analysis calcd. for C.sub.21H.sub.32N.sub.4O.sub.1Pt.0.5H.sub.2O: C: 35.80, H: 4.72, N: 7.95, found: C: 36.11, H: 4.68, N: 7.63.

(OC-6-44)-Acetatodiamminedichlorido[5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentylcarbamato]platinum(IV) (30; KP2540)

(35) The compound was synthesized from (OC-6-44)-acetatodiamminedichloridohydroxidoplatinum(IV) (4; 322 mg, 0.86 mmol) and 1-(5-isocyanatopentyl)-1H-pyrrole-2,5-dione (2 eq., 356 mg, 1.71 mmol) in 5 mL DMF (abs.) according to the general procedure. Purification via preparative RP-HPLC, isocratic with 25% methanol, yielded a pale yellow solid. Yield: 165.0 mg (33%); .sup.1H-NMR (DMSO-d6): δ=7.01 (s, 2H, CH), 6.89-6.34 (m, 6H, NH.sub.3), 6.54 (br, 1H, NH), 3.38 (t, J=7.1 Hz, 2H, NCH.sub.2), 2.96-2.80 (m, 2H, NHCH.sub.2), 1.91 (s, 3H, CH.sub.3), 1.47 (quint, J=7.3 Hz, 2H, CH.sub.2), 1.41-1.30 (m, 2H, CH.sub.2), 1.24-1.14 (m, 2H, CH.sub.2) ppm; HRMS (ESI-TOF): calcd. for [C.sub.12H.sub.22Cl.sub.2N.sub.4O.sub.6Pt—Na.sup.+].sup.+: 607.0454, found: 607.0453; elemental analysis calcd. for C.sub.12H.sub.22Cl.sub.2N.sub.4O.sub.6Pt: C: 24.67, H: 3.80, N: 9.59, found: C: 24.58, H: 3.90, N: 9.29.

(OC-6-34)-Acetatodiamminecyclobutane-1,1-dicarboxylato[5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentylcarbamato]platinum(IV) (31)

(36) The compound was synthesized from (OC-6-44)-acetatodiamminecyclobutane-1,1-dicarboxylatohydroxidoplatinum(IV) (29; 41.0 mg, 101.2 μmol) and 1-(5-isocyanatopentyl)-1H-pyrrole-2,5-dione (2 eq., 42.1 mg, 202.3 μmol) in 2 mL DMF (abs.) according to the general procedure. Purification via preparative RP-HPLC, isocratic with 18% acetonitrile, yielded a white solid. Yield: 30.1 mg (51%); 1H-NMR (DMSO-d6): δ=7.07-6.67 (m, 3H, NH.sub.3), 6.99 (s, 2H, CH), 6.44-6.00 (m, 3H, NH.sub.3), 6.38 (br, 1H, NH), 3.36 (t, J=7.1 Hz, 2H, NCH.sub.2), 2.96-2.78 (m, 2H, NHCH.sub.2), 2.69-2.54 (m, 3H, CH.sub.2CCH.sub.2), 2.25-2.13 (m, 1H, CH.sub.2CCH.sub.2), 1.94 (s, 3H, CH.sub.3), 1.87-1.73 (m, 2H, NCH.sub.2CH.sub.2), 1.51-1.40 (m, 2H, CH.sub.2), 1.39-1.28 (m, 2H, CH.sub.2), 1.23-1.11 (m, 2H, CH.sub.2) ppm; ESI-MS: calcd. for [Cl.sub.8H.sub.28N.sub.4O.sub.10Pt—Na.sup.+].sup.+: 678.13, found: 678.34.

(37) Compounds 21 and 32 to 42 can be prepared in accordance with the synthesis procedures described in the general part of the present specification:

(38) ##STR00052## ##STR00053## ##STR00054##

Example 2: RP-HPLC Stability Studies of Compound 12 (KP2299)

(39) The stability of the compounds of the invention in aqueous solutions at different pH values was evaluated by incubation of compound 12 (KP2299) in different buffers and subsequent monitoring of the decrease of the compound peak area with the UV/VIS detector of a RP-HPLC system at 250 nm. Therefore, compound 12 was dissolved at a concentration of 0.5 mM in either 100 mM phosphate buffer pH=7.4, 100 mM sodium acetate buffer pH=6.3, 100 mM sodium acetate buffer pH=5.3 or 100 mM sodium acetate buffer pH=4.3 and incubated at 20° C. for 24 hours. All the measurements were carried out on an Ultimate 3000 RS system (Thermo Scientific, Waltham, Mass., USA) controlled by Chromeleon 7.2 SR4 software using an Acquity BEH C18 reversed phase column (50×3.0 mm, 1.7 μm particle size) from Waters (Milford, USA). Following conditions were used for the runs: flow rate 0.6 mL/min, sampler temperature: 20° C., column oven temperature 25° C., injection volume 10 μL, gradient 5-95% MeOH (and H.sub.2O (+0.1% HCOOH)) in 10 min. The compound was first measured directly after the preparation of the compound (after 2-3 min) and thereafter every 60 min. The decrease of the compound was calculated by the compound peak areas relatively to the peak area directly after the preparation of the compound. It was found that the compound is stable at pH=4.3 and pH=5.3 without significant changes over 24 h. At pH=6.3 the hydrolysis is below 0.5%/h, whereas at pH=7.4 the hydrolysis is quite fast with ˜2.6%/h (see FIG. 5). Corresponding results can be obtained when the further compounds of the invention are tested. It has thus been found that the compounds of the present invention, including KP2299, are particularly stable at a pH of about 4 to 6. Hence, the compounds of formula (I) according to the invention can advantageously be provided in the form of a liquid aqueous composition having a pH of 4 to 6 (particularly a pH of about 5), or as a solid composition for rehydration having a pH of 4 to 6 (particularly a pH of about 5) when rehydrated.

Example 3: In Vivo Assays for Anticancer Activity

(40) CT-26 Experiments:

(41) CT-26 colon cancer cells (5×10.sup.5 in serum-free medium) were injected subcutaneously into the right flank of Balb/c mice. Animals were treated with the indicated oxaliplatin-releasing drugs at concentrations equimolar to 9 mg/kg oxaliplatin (i.v.; KP2156, KP2299 (compound 12), and KP2541 (compound 22) were dissolved in 0.9% NaCl solution, KP2260 (compound 11) was dissolved in 10% propylene glycol/0.9% NaCl and oxaliplatin was dissolved in 5% glucose solution according to the clinical protocol) twice a week (Mondays and Thursdays). Also in case of KP2552 (mixture of compounds 23 and 24, with the 4-methyl-1,2-cyclohexanediamine moiety) the solvent and application scheme of oxaliplatin was used. In case of cisplatin-releasing prodrugs KP2372 (compound 8) and KP2540 (compound 30), a dose equimolar to 3 mg/kg cisplatin was applied twice a week. For the carboplatin derivative KP2551 (compound 20) a dose equimolar to 12 mg/kg carboplatin was applied. The complexes were dissolved in 0.9% NaCl, while for the platinum(II) drugs 5% glucose solution was used according to the clinical protocol. Animals were controlled for distress development every day and tumor size was assessed regularly by caliper measurement. Tumor volume was calculated using the formula: (length×width.sup.2).

(42) B16 Experiments:

(43) B16 melanoma cells (1×10.sup.5 in serum-free medium) were injected subcutaneously into the right flank of male C57/B6JRj mice. Animals were treated with KP2299 at concentrations equimolar to 9 mg/kg oxaliplatin (i.v.; dissolved in 0.9% NaCl solution) twice a week. Oxaliplatin was dissolved in 5% glucose solution according to the clinical protocol. Animals were controlled for distress development every day and tumor size was assessed regularly by caliper measurement. Tumor volume was calculated using the formula: (length×width.sup.2).

(44) L1210 Experiments:

(45) L1210 murine leukemia cells (1×10.sup.5) were injected intraperitoneally in a volume of 0.2 mL into female DBA/2J (cisplatin-releasing drugs) or male DBA/2J×Balb/c SCID F1 mice (oxaliplatin-releasing drugs). Compounds (see FIG. 4; dissolved as described above) were administered intraperitoneally at drug concentrations equimolar to 3 mg/kg cisplatin and 9 mg/kg oxaliplatin, respectively, on day 1, 5, and 9. Toxicity was monitored by daily observation of animals and registration of their body weight. Therapeutic efficacy of the drug candidate was monitored by recording the lengths of survival of experimental mice compared to untreated control animals.

(46) Results:

(47) One of the mono-functionalized oxaliplatin derivatives (KP2299) revealed exceptionally increased anticancer activity compared to oxaliplatin (see FIGS. 1A and 2 for CT-26 and FIG. 3 for B16 tumors) and to the bismaleimide compound KP2156 (see FIG. 1B). It is noteworthy that this activity was especially pronounced in female mice (see FIG. 2), where treatment resulted in complete remission in 3 out of 4 animals. This is remarkable as the very similar mono-functionalized analogue KP2260 (see FIG. 1C), the oxaliplatin-analogue KP2541 which lacks the NH-group in the linker (see FIGS. 1E and 1F) as well as the 4-methyl-1,2-cyclohexanediamine derivative KP2552 were far less or at least later active than KP2299 (see FIG. 1G). In addition, the cisplatin analogues KP2372 (see FIG. 1D) and KP2540 were widely inactive (see FIGS. 1E and 1F). In contrast, the carboplatin prodrug KP2551 had very strong anticancer activity resulting in complete remissions in 2/4 animals. This was especially remarkable as carboplatin in equimolar concentration had no impact on CT-26 tumor growth at all (see FIG. 1G).

(48) In addition to these promising effects in solid cancer models, also in a leukemia model (L1210) distinctly enhanced anticancer activity resulting in cure of several animals was observed. In contrast, free oxaliplatin resulted only in life prolongation in ˜50% of the treated animals (see FIG. 4). Again, the cisplatin-releasing derivatives did not show effects superior to free cisplatin. These anti-leukemic effects are unexpected, as maleimide-functionalized drugs are supposed to specifically target the solid tumor tissue due to the so-called enhanced permeability and retention effect (EPR effect).

(49) It has thus been demonstrated that the compounds of formula (I) according to the present invention, including in particular the compounds KP2299 (compound 12) and KP2551 (compound 20), are highly effective in the therapy of cancer, including colon cancer, melanoma and leukemia.